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A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia

Abstract

Methotrexate (MTX) is an important component of therapy used to treat childhood acute lymphoblastic leukemia (ALL). Two single-nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, affect MTHFR activity. A large body of studies has investigated the potential role of MTHFR SNPs in MTX toxicity in pediatric ALL. However, the results are controversial. In this review and meta-analysis, we critically evaluate the relationship between the C677T and A1298C polymorphisms of MTHFR and MTX toxicity in pediatric ALL. The majority of published reports do not find associations between MTHFR polymorphisms and toxicity in pediatric ALL. When associations are reported, often the results are contradictory to each other. The meta-analysis confirms a lack of association. In conclusion, MTHFR, C677T and A1298C polymorphisms do not seem to be good markers of MTX-related toxicity in pediatric ALL.

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References

  1. Koppen IJ, Hermans FJ, Kaspers GJ . Folate related gene polymorphisms and susceptibility to develop childhood acute lymphoblastic leukaemia. Br J Haematol 2010; 148: 3–14.

    Article  CAS  PubMed  Google Scholar 

  2. Johnston WT, Lightfoot TJ, Simpson J, Roman E . Childhood cancer survival: a report from the United Kingdom Childhood Cancer Study. Cancer Epidemiol 2010; 34: 659–666.

    Article  PubMed  Google Scholar 

  3. Pui CH, Robison LL, Look AT . Acute lymphoblastic leukaemia. Lancet 2008; 371: 1030–1043.

    Article  CAS  Google Scholar 

  4. Imanishi H, Okamura N, Yagi M, Noro Y, Moriya Y, Nakamura T et al. Genetic polymorphisms associated with adverse events and elimination of methotrexate in childhood acute lymphoblastic leukemia and malignant lymphoma. J Hum Genet 2007; 52: 166–171.

    Article  CAS  PubMed  Google Scholar 

  5. Gorlick R, Goker E, Trippett T, Waltham M, Banerjee D, Bertino JR . Intrinsic and acquired resistance to methotrexate in acute leukemia. N Engl J Med 1996; 335: 1041–1048.

    Article  CAS  Google Scholar 

  6. Krajinovic M, Moghrabi A . Pharmacogenetics of methotrexate. Pharmacogenomics 2004; 5: 819–834.

    Article  CAS  PubMed  Google Scholar 

  7. Swerts K, De Moerloose B, Dhooge C, Laureys G, Benoit Y, Philippé J . Prognostic significance of multidrug resistance-related proteins in childhood acute lymphoblastic leukaemia. Eur J Cancer 2006; 42: 295–309.

    Article  CAS  PubMed  Google Scholar 

  8. Treviño LR, Shimasaki N, Yang W, Panetta JC, Cheng C, Pei D et al. Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J Clin Oncol 2009; 27: 5972–5978.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Abe T, Unno M, Onogawa T, Tokui T, Kondo TN, Nakagomi R et al. LST-2, a human liver-specific organic anion transporter, determines methotrexate sensitivity in gastrointestinal cancers. Gastroenterology 2001; 120: 1689–1699.

    Article  CAS  PubMed  Google Scholar 

  10. De Mattia E, Toffoli G . C677T and A1298C MTHFR polymorphisms, a challenge for antifolate and fluoropyrimidine-based therapy personalisation. Eur J Cancer 2009; 45: 1333–1351.

    Article  CAS  PubMed  Google Scholar 

  11. Cheok MH, Evans WE . Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy. Nat Rev Cancer 2006; 6: 117–129.

    Article  CAS  PubMed  Google Scholar 

  12. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111–113.

    Article  CAS  PubMed  Google Scholar 

  13. Weisberg IS, Jacques PF, Selhub J, Bostom AG, Chen Z, Curtis Ellison R et al. The 1298A—>C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. Atherosclerosis 2001; 156: 409–415.

    Article  CAS  Google Scholar 

  14. Huang L, Tissing WJ, de Jonge R, van Zelst BD, Pieters R . Polymorphisms in folate-related genes: association with side effects of high-dose methotrexate in childhood acute lymphoblastic leukemia. Leukemia 2008; 22: 1798–1800.

    Article  CAS  PubMed  Google Scholar 

  15. Lopez-Lopez E, Martin-Guerrero I, Ballesteros J, Piñan MA, Garcia-Miguel P, Navajas A et al. Polymorphisms of the SLCO1B1 gene predict methotrexate-related toxicity in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2011; 57: 612–619.

    Article  PubMed  Google Scholar 

  16. Kantar M, Kosova B, Cetingul N, Gumus S, Toroslu E, Zafer N et al. Methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms and therapy-related toxicity in children treated for acute lymphoblastic leukemia and non-Hodgkin lymphoma. Leuk Lymphoma 2009; 50: 912–917.

    Article  CAS  PubMed  Google Scholar 

  17. Liu SG, Li ZG, Cui L, Gao C, Li WJ, Zhao XX . Effects of methylenetetrahydrofolate reductase gene polymorphisms on toxicities during consolidation therapy in pediatric acute lymphoblastic leukemia in a Chinese population. Leuk Lymphoma 2011; 52: 1030–1040.

    Article  CAS  PubMed  Google Scholar 

  18. Shimasaki N, Mori T, Samejima H, Sato R, Shimada H, Yahagi N et al. Effects of methylenetetrahydrofolate reductase and reduced folate carrier 1 polymorphisms on high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia or lymphoma. J Pediatr Hematol Oncol 2006; 28: 64–68.

    Article  CAS  PubMed  Google Scholar 

  19. Karathanasis NV, Stiakaki E, Goulielmos GN, Kalmanti M . The role of the methylenetetrahydrofolate reductase 677 and 1298 polymorphisms in Cretan children with acute lymphoblastic leukemia. Genet Test Mol Biomarkers 2011; 15: 5–10.

    Article  CAS  PubMed  Google Scholar 

  20. Pakakasama S, Kanchanakamhaeng K, Kajanachumpol S, Udomsubpayakul U, Sirachainan N, Thithapandha A et al. Genetic polymorphisms of folate metabolic enzymes and toxicities of high dose methotrexate in children with acute lymphoblastic leukemia. Ann Hematol 2007; 86: 609–611.

    Article  PubMed  Google Scholar 

  21. Aplenc R, Thompson J, Han P, La M, Zhao H, Lange B et al. Methylenetetrahydrofolate reductase polymorphisms and therapy response in pediatric acute lymphoblastic leukemia. Cancer Res 2005; 65: 2482–2487.

    Article  CAS  PubMed  Google Scholar 

  22. Erčulj N, Kotnik BF, Debeljak M, Jazbec J, Dolžan V . Influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in childhood acute lymphoblastic leukemia. Leuk Lymphoma 2012; 53: 1096–1104.

    Article  PubMed  Google Scholar 

  23. Faganel Kotnik B, Grabnar I, Bohanec Grabar P, Dolžan V, Jazbec J . Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma. Eur J Clin Pharmacol 2011; 67: 993–1006.

    Article  CAS  PubMed  Google Scholar 

  24. Faganel Kotnik B, Dolzan V, Grabnar I, Jazbec J . Relationship of the reduced folate carrier gene polymorphism G80A to methotrexate plasma concentration, toxicity, and disease outcome in childhood acute lymphoblastic leukemia. Leuk Lymphoma 2010; 51: 724–726.

    Article  CAS  PubMed  Google Scholar 

  25. Salazar J, Altés A, Del Río E, Estella J, Rives S, Tasso M et al. Methotrexate consolidation treatment according to pharmacogenetics of MTHFR ameliorates event-free survival in childhood acute lymphoblastic leukaemia. Pharmacogenomics J 2011; 12: 379–385.

    Article  PubMed  Google Scholar 

  26. Tantawy AA, El-Bostany EA, Adly AA, Abou El Asrar M, El-Ghouroury EA, Abdulghaffar EE . Methylene tetrahydrofolate reductase gene polymorphism in Egyptian children with acute lymphoblastic leukemia. Blood Coagul Fibrinolysis 2010; 21: 28–34.

    Article  CAS  PubMed  Google Scholar 

  27. Horinouchi M, Yagi M, Imanishi H, Mori T, Yanai T, Hayakawa A et al. Association of genetic polymorphisms with hepatotoxicity in patients with childhood acute lymphoblastic leukemia or lymphoma. Pediatr Hematol Oncol 2010; 27: 344–354.

    Article  CAS  PubMed  Google Scholar 

  28. Costea I, Moghrabi A, Laverdiere C, Graziani A, Krajinovic M . Folate cycle gene variants and chemotherapy toxicity in pediatric patients with acute lymphoblastic leukemia. Haematologica 2006; 91: 1113–1116.

    CAS  PubMed  Google Scholar 

  29. Chatzidakis K, Goulas A, Athanassiadou-Piperopoulou F, Fidani L, Koliouskas D, Mirtsou V . Methylenetetrahydrofolate reductase C677T polymorphism: association with risk for childhood acute lymphoblastic leukemia and response during the initial phase of chemotherapy in greek patients. Pediatr Blood Cancer 2006; 47: 147–151.

    Article  PubMed  Google Scholar 

  30. van Kooten Niekerk PB, Schmiegelow K, Schroeder H . Influence of methylene tetrahydrofolate reductase polymorphisms and coadministration of antimetabolites on toxicity after high dose methotrexate. Eur J Haematol 2008; 81: 391–398.

    CAS  PubMed  Google Scholar 

  31. Sepe DM, McWilliams T, Chen J, Kershenbaum A, Zhao H, La M et al. Germline genetic variation and treatment response on CCG-1891. Pediatr Blood Cancer 2012; 58: 695–700.

    Article  PubMed  Google Scholar 

  32. El-Khodary NM, El-Haggar SM, Eid MA, Ebeid EN . Study of the pharmacokinetic and pharmacogenetic contribution to the toxicity of high-dose methotrexate in children with acute lymphoblastic leukemia. Med Oncol 2011; 29: 2053–2062.

    Article  PubMed  Google Scholar 

  33. Krajinovic M, Lemieux-Blanchard E, Chiasson S, Primeau M, Costea I, Moghrabi A . Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics J 2004; 4: 66–72.

    Article  CAS  PubMed  Google Scholar 

  34. Kishi S, Cheng C, French D, Pei D, Das S, Cook EH et al. Ancestry and pharmacogenetics of antileukemic drug toxicity. Blood 2007; 109: 4151–4157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. D'Angelo V, Ramaglia M, Iannotta A, Crisci S, Indolfi P, Francese M et al. Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia and MTHFR polymorphisms as pharmacogenetic determinants. Cancer Chemother Pharmacol 2011; 68: 1339–1346.

    Article  CAS  PubMed  Google Scholar 

  36. Kishi S, Griener J, Cheng C, Das S, Cook EH, Pei D et al. Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia. J Clin Oncol 2003; 21: 3084–3091.

    Article  CAS  PubMed  Google Scholar 

  37. Shimasaki N, Mori T, Torii C, Sato R, Shimada H, Tanigawara Y et al. Influence of MTHFR and RFC1 polymorphisms on toxicities during maintenance chemotherapy for childhood acute lymphoblastic leukemia or lymphoma. J Pediatr Hematol Oncol 2008; 30: 347–352.

    Article  CAS  PubMed  Google Scholar 

  38. Lopez-Lopez E, Ballesteros J, Garcia-Orad A . MTHFR 677TT genotype and toxicity of methotrexate: controversial results. Cancer Chemother Pharmacol 2011; 68: 1369–1370, author reply 1371.

    Article  PubMed  Google Scholar 

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Acknowledgements

This project was supported by RTICC (RD/06/0020/0048), Basque Government (GIC10/71, SAI10/03) and UPV/EHU (UFI11/35). ELL was supported by a predoctoral grant from the Basque Government.

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Correspondence to A Garcia-Orad.

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Lopez-Lopez, E., Martin-Guerrero, I., Ballesteros, J. et al. A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia. Pharmacogenomics J 13, 498–506 (2013). https://doi.org/10.1038/tpj.2012.44

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